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Los tumores neuroendocrinos gastroentropancreáticos derivan de las células neuroendocrinas dispersas a través del tracto gastrointestinal y del páncreas endocrino. El desarrollo embriológico del páncreas es un proceso complejo que se inicia a partir de células madre pluriplotenciales que provienen del endodermo, y que atraviesa 2 fases: la primera transición, en la que la célula madre se diferencia en células exocrinas y endocrinas y que está mediada por factores de transcripción como Pdx1 (insulin promoter factor 1), Hlxb6 y SOX9, y la segunda transición, en la que la célula madre neuroendocrina se diferencia en los 5 tipos celulares del páncreas: células α, β, δ, PP y ¿. Este proceso está modulado por un equilibrio entre factores que favorecen la diferenciación, el más importante neurogenina 3, y factores inhibidores que dependen de las señales de Nocht. Se postula la existencia de una tercera transición en el páncreas posnatal en el que las células madre de los conductos pancreáticos se convertirían en células β adultas, mediante autoduplicación o neogénesis.
En el intestino delgado del adulto las células madre se sitúan en las criptas intestinales y se diferencian hacia los villi en líneas secretoras (enterocitos, células caliciformes y células de Paneth) o neuroendocrinas de las que dependen al menos 10 tipos celulares. Este proceso está regulado por factores de transcripción como Math1, neurogenina 3 y NeuroD.
Palabras clave:
Células madre neuroendocrinas
Neurogenina 3
Señales de Nocth
Síndrome de diarrea malabsortiva congénita
Gastroenteropancreatic neuroendocrine tumours (GEP NETs) originate from the neuroendocrine cells through the gastrointestinal tract and endocrine pancreas. The embryologic development of the pancreas is a complex process that begins with the “stem cell” that come from the endodermus. These cells go through two phases: in the first transition the “stem cell” differentiates in exocrine and endocrine cells. This process is regulated by transcription factors such as Pd×1 (“insulin promoter factor 1”), Hlxb6 and SOX9. In the second transition the neuroendocrine cell differentiates in the 5 cell types (α, β, δ, PP y ¿.). This process is regulated through the balance between factors favoring differentiation (mainly neurogenin 3) and inhibitor factors which depend on Notch signals. The existence of a third transition in postnatal pancreas is hypothesized. The “stem cell” from pancreatic ducts would become adult β cells, through autoduplication and neogenesis.
In the small gut of the adult the stem cell are placed in the intestinal crypts and develop to villi in secretor lines (enterocytes, globet and Paneths cells) or neuroendocrine cells from which at least 10 cell types depend. This process is regulated by transcription factors: Math1, neurogenina 3 and NeuroD.
Key words:
Neuroendocrine “stem cell”
Neurogenin 3
Notch signals
Congenital malabsorptive diarrhea
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Bibliografía
[1.]
S. Oberndorfern.
Karzinoide tumoren des dünndars.
Frank Z Pathol, 1 (1907), pp. 426-432
[2.]
G. Klöpplel.
Tumor biology and histopathology of neuroendocrine tumours.
Best Pract Res Clin Endocrinol Metab, 21 (2007), pp. 15-31
[3.]
P. Bech, V. Winstanley, K. Murphy, A. Sam, K. Meeran, M. Ghatei, S. Bloom.
Elevated cocaine- and amphetamine-regulated transcript immunoreactivity in the circulation of patients with neuroendocrine malignan.
J Clin Endocrinol Metab, 23 (2008), pp. 1246-1253
[4.]
R. Heidenhain.
Untersucungen über den Bau der LAbdrüsen.
Arch f milr Ant, 6 (1870), pp. 368
[5.]
Langerhans Püber die heutigen Bewohner des heiligen Landes. Braunschweig. Archiv für Anthropologie. 1873;6:39-58, 201-12.
[6.]
M. Ciaccio.
Sur une nouvelle espèce cellulaire dans les glandes de Lieberkühn.
C R Senaces Soc Biol Fil (París), 60 (1906), pp. 70-77
[7.]
A. Gosset, P. Masson.
Tumeuers endocrines de l’apendice.
Presse Med, 25 (1914), pp. 237-240
[8.]
F. Feyrter.
Uber diffuse endockrine epitheliale Organe.
Zentralb Innere Med, 545 (1938), pp. 32-41
[9.]
A. Pearse.
The diffuse endocrine system and tehe implications of the APUD concept.
Int Surg, 64 (1976), pp. 5-7
[10.]
A. Pearse.
The calcitonin secreting C cells and their relationship to the APUD cell series.
J Endocrinol, 45 (1969), pp. 13-14
[11.]
S. Kim, E. Rulifson.
Conserved mechanisms of glucose sensing and regulation by Drosophila corpora cardiaca cells.
Nature, 431 (2004), pp. 316-320
[12.]
J.E. Lee, S.M. Hollenberg, L. Snider, D.L. Turner, N. Lipnick, H. Weintraub.
Conversion of Xenopus ectoderm into neurons by NeuroD, a basic helix-loop-helix protein.
Science, 268 (1995), pp. 836-844
[13.]
A. Andrew, B. Kramer, B.B. Rawdon.
The origin of gut and pancreatic neuroendocrine (APUD) cells —the last word?.
J Pathol, 186 (1976), pp. 117-118
[14.]
J. Fontaine, C. Le Lievre, N.M. Le Douarin.
What is the developmental fate of the neural crest cells which migrate into the pancreas in the avian embryo?.
Gen Comp Endocrinol, 33 (1977), pp. 394-404
[15.]
N.M. Le Douarin, M.A. Teillet.
The migration of neural crest cells to the wall of the digestive tract in avian embryo.
J Embryol Exp Morphol, 30 (1973), pp. 31-48
[16.]
N.M. Le Douarin.
On the origin of pancreatic endocrine cells.
Cell, 53 (1988), pp. 169-171
[17.]
H. Field, P. Dong, D. Beis, R. Stainer.
Formation of the digestive system in zebrafish.
Developm Biology, 281 (2003), pp. 197-208
[18.]
M.C. Jørgensen, J. Ahnfelt-Rønne, J. Hald, O. Madsen, P. Serup, J. Hecksher-Sørensen.
An illustrated review of early pancreas development in the mouse.
Endocrine Rev, 28 (2007), pp. 685-705
[19.]
S. McDonald, S.L. Preslon, L. Greaves, S. Leedahm, M. Lovell, J. Jankowski, et al.
Clonal expansion in the human gut: mitochondrial DNA mutations show us the way.
Cell Cycle, (2006), pp. 808-811
[20.]
W.J. Rutter, J.D. Kemp, W.S. Bradshaw, W.R. Clark, R.A. Ronzio, T.G. Sanders.
Regulation of specific protein synthesis in cytodifferentiation.
J Cell Physiol, 72 (1968), pp. 1-18
[21.]
R.L. Pictet, W.R. Clark, R.H. Williams, W.J. Rutter.
An ultrastructural analysis of the developing embryonic pancreas.
Dev Biol, 29 (1972), pp. 436-467
[22.]
A. Kubo, K. Shinozaki, J.M. Shannon, V. Kouskoff, M. Kennedy, S. Woo, et al.
Development of definitive endoderm from embryonic stem cells in culture.
Development, 131 (2004), pp. 1651-1662
[23.]
K.A. D’Amour, A.D. Agulnick, S. Eliazer, O.G. Kelly, E. Kroon, E.E. Baetge.
Efficient differentiation of human embryonic stem cells to definitive endoderm.
Nat Biotechnol, 23 (2005), pp. 1534-1541
[24.]
K.A. D’Amour, A.G. Bang, S. Eliazer, O.G. Kelly, A.D. Agulnick, N.G. Smart, et al.
Production of pancreatic hormone-expressing endocrine cells from human embryonic stem cells.
Nat Biotechnol, 24 (2006), pp. 1392-1401
[25.]
G.K. Gittes, P.E. Galante, D. Hanahan, W.J. Rutter, H.T. Debase.
Lineage-specific morphogenesis in the developing pancreas: role of mesenchymal factors.
Development, 122 (1996), pp. 439-447
[26.]
C.L. Prado, A.E. Pugh-Bernard, L. Elghazi, B. Sosa-Pineda, L. Sussel.
Ghrelin cells replace insulin-producing beta cells in two mouse models of pancreas development.
Proc Natl Acad Sci U S A, 101 (2004), pp. 2924-2929
[27.]
L.C. Murtaugh.
Pancreas and beta-cell development: from the actual to the possible.
Development, 134 (2007), pp. 427-438
[28.]
J.M. Wells, D.A. Melton.
Early mouse endoderm is patterned by soluble factors from adjacent germ layers.
Development, 127 (2000), pp. 1563-1572
[29.]
Y. Dor, J. Brown, O. Martinez, D. Melton.
Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation.
Nature, 429 (2006), pp. 41-46
[30.]
E. Hao, B. Tyrberg, P. Itkin-Ansari, J. Lakey, I. Geron, E. Monosov, et al.
Beta-cell differentiation from nonendocrine epithelial cells of the adult human pancreas.
Nat Med, 12 (2006), pp. 310-316
[31.]
H. Ohlsson, K. Karlsson, T. Edlund.
IPF1, a homeodomain-containing transactivator of the insulin gene.
EMBO J, 12 (1993), pp. 4251-4259
[32.]
J. Jonsson, L. Carlsson, T. Edlund, H. Edlund.
Insulin-promoterfactor 1 is required for pancreas development in mice.
Nature, 371 (1994), pp. 606-609
[33.]
M.F. Offield, T.L. Jetton, P.A. Labosky, M. Ray, R.W. Stein, M.A. Magnuson, et al.
PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum.
Development, 122 (1996), pp. 983-995
[34.]
D.A. Stoffers, J. Ferrer, W.L. Clarke, J.F. Habener.
Early-onset type- II diabetes mellitus (MODY4) linked to IPF1.
Nat Genet, 17 (1997), pp. 138-139
[35.]
H. Li, S. Arber, T.M. Jessell, H. Edlund.
Selective agenesis of the dorsal pancreas in mice lacking homeobox gene Hlxb9.
Nat Genet, 23 (1999), pp. 67-70
[36.]
P. Seymur, K. Freude, K. Tran, E. Mayes, J. Jensen, R. Kist, et al.
From the Cover: SOX9 is required for maintenance of the pancreatic progenitor cell pool.
PNAS, 104 (2007), pp. 1865-1870
[37.]
L. Sommer, Q. Ma, D.J. Anderson.
Neurogenins, a novel family of atonal-related bHLH transcription factors, are putative mammalian neuronal determination genes that reveal progenitor cell heterogeneity in the developing CNS and PNS.
Mol Cell Neurosci, 8 (1996), pp. 221-241
[38.]
J. Lee, Y. Wu, Y. Qi, H. Xue, Y. Liu, D. Scheel, et al.
Neurogenin 3 participates in gliogenesis in the developing vertebral spinal cord.
Dev Biol, 253 (2003), pp. 84-98
[39.]
V.M. Schwitzgebel, D.W. Scheel, J.R. Conners, J. Kalamaras, J.E. Lee, D.J. Anderson, et al.
Expression of neurogenin3 reveals an islet cell precursor population in the pancreas.
Development, 127 (2000), pp. 3533-3542
[40.]
G. Gradwohl, A. Dierich, M. LeMeur, F. Guillemot.
Neurogenin3 is required for the development of the four endocrine cell lineages of the pancreas.
Proc Natl Acad Sci U S A., 97 (2000), pp. 1607-1611
[41.]
L. Del Bosque-Plata, J. Lin, J. Horikawa, P. Schwarz, N. Cox, N. Iwasaki, et al.
Mutations in the coding region of the neurogenin 3 gene (NEUROG3) are not a common cause of maturityonset diabetes of the young in japanese subjects.
Diabetes, 50 (2006), pp. 694-696
[42.]
M. Malecki, M. Jhala, U. Antonellis, L. Fields, A. Doria, T. Orban, et al.
Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus.
Nature Genetics, 23 (1999), pp. 323-328
[43.]
J. Wang, G. Cortina, S.V. Wu, R. Tran, J.H. Cho, M.H. Tsay, et al.
Mutant neurogenin-3 in congenital malabsorptive diarrhea.
NEJM, 355 (2006), pp. 270-280
[44.]
L.C. Murtaugh.
Pancreas and beta-cell development: from the actual to the possible.
Development, 134 (2007), pp. 427-438
[45.]
L. Sussel, J. Kalamaras, D. Hartigan-O’Connor, J. Meneses, R. Pedersen, et al.
Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells.
Development, 125 (1998), pp. 2213-2221
[46.]
M. Sander, A. Neubuser, J. Kalamaras, G.R. Martin, M.S. German.
Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development.
Genes Dev, 11 (1997), pp. 1662-1673
[47.]
L. St-Onge, B. Sosa-Pineda, K. Chowdhury, A. Mansouri, P. Gruss.
Pax6 is required for differentiation of glucagon-producing - cells in mouse pancreas.
Nature, 387 (1997), pp. 406-409
[48.]
M.A. Hussain, J. Lee, C.P. Miller, J.F. Habener.
POU domain transcription factor brain 4 confers pancreatic a-cell-specific expre ssion of the proglucagon gene through interaction with a novel proximal promoter G1 element.
Mol Cell Biol, 17 (1997), pp. 7186-7194
[49.]
A. Apelviqvist, Li. Hao, L. Sommer, P. Beatus, D. Anderson, T. Honjot, et al.
Notch signalling cotrols pancreatic cell deifferentation.
Nature, 400 (1999), pp. 877-880
[50.]
E.C. Lai.
Notch signaling:control of cell communication and cell fate.
Development, 131 (2004), pp. 965-973
[51.]
J. Jensen, E. Pedersen, P. Galante, J. Hald, R.S. Heller, M. Ishibashi, et al.
Control of endodermal endocrine development by Hes-1. Nat.
Genet, 24 (2000), pp. 36-44
[52.]
F. Esni, B. Johansson, G. Radice, H. Semb.
Dorsal pancreas a agenesis in N- cadherin-deficient mice.
Dev Biol, 238 (2002), pp. 202-212
[53.]
F. Sanvito, P. Herrera, J. Huarte, A. Nichols, R. Montesano, L. Orci, et al.
TGF-beta 1 influences the relative development of the exocrine and endocrine pancreas in vitro.
Development, 120 (1994), pp. 3451-3462
[54.]
M. Kunnimalaiyaan, K. Traeger, H. Chen.
Conservation of the Notch1 signaling pathway in gastrointestinal carcinoid cells.
Am J Physiol Gastrointest Liver Physiol, 289 (2005), pp. G636-G642
[55.]
E. Nakakura, V. Sriuranpong, M. Kunnimalaiyaan, E. Hsiao, K. Schuebel, M. Borges, et al.
Regulation of neuroendocrine differentiation in gastrointestinal carcinoid tumor cells by notch signaling.
J Clin Endocrinol and Metab, 90 (2005), pp. 4350-4356
[56.]
R.N. Wang, G. Kloppel, L. Bouwens.
Duct- to islet-cell differentiation and islet growth in the pancreas of duct-ligated adult rats.
Diabetologia, 38 (1995), pp. 1405-1411
[57.]
G.H. Starich, M. Zafirova, R. Jablenska, P. Petkov, C.K. Lardinois.
A morphological and immunohistochemical investigation of endocrine pancreata from obese ob+/ob+ mice.
Acta Histochemica, 90 (1991), pp. 93-101
[58.]
Y. Dor, J. Brown, O.I. Martinez, D.A. Melton.
Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation.
Nature, 429 (2004), pp. 41-46
[59.]
M. Zhao, S. Amiel, M. Christie, P. Muisan, P. Srnivasan, W. Littlejonh, et al.
Evidence for the presence of stem cell-like progenitor cells in human adult pancreas.
J Endocrinol, 195 (2007), pp. 407-414
[60.]
B. Soria, E. Roche, G. Berna, T. Leon-Quinto, J.A. Reig, F. Martin.
Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin-induced diabetic mice.
Diabetes, 49 (2000), pp. 157-162
[61.]
S. Assady, G. Maor, M. Amit, J. Itskovitz-Eldor, K. Skorecky, M. Tzukerman.
Insulin prodcution by human embrionic stem cells.
Diabetes, 50 (2001), pp. 1691-1697
[62.]
L. Farilla, A. Bulotta, B. Hirshberg, S. Li Calzi, N. Khoury, H. Noushmehr, et al.
Glucagon-Like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets.
Endocrinology, 144 (2003), pp. 5149-5158
[63.]
M. Eberhardt, P. Salmon, M.A. von Mach, J.G. Hengstler, M. Brulport, H. Zulewski.
Multipotential nestin and Isl-1 positive mesenchymal stem cells isolated from human pancreatic islets.
Biochem Biophys Res Commun, 345 (2006), pp. 1167-1176
[64.]
S.E. Schonhoff, M. Giel-Moloney, A.B. Leiter.
Minireview: development and differentiation of gut endocrine cells.
Endocrinology, 145 (2004), pp. 2639-2644
[65.]
H. Cheng, C.P. Leblond.
Origin, differentiation, and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian theory of the origin of of the origin of the four epithelial cell types.
Am J Anat, 141 (1974), pp. 537-562
[66.]
N. Wrigth.
The origin of the gut neuroendocrine cells.
A century of advances in neuroendocrne tumor biology and treatment, pp. 192-199
[67.]
K.A. Roth, J.M. Hertz, J.I. Gordon.
Mapping enteroendocrine cell populations in transgenic mice reveals an unexpected degree of complexity in cellular differentiation within the gastrointestinal tract.
J Cell Biol, 110 (1990), pp. 1791-1801
[68.]
M.R. Novelli, J.A. Williamsin, I.P. Tomlinson.
Polyclonal origin of colonic adenomas in a X0/XY patient with FAP.
Science, 272 (1996), pp. 1187-1190
[69.]
M.R. Novelli, A. Cossu, D. Oukrif.
X-inactivation pacht size in human fetal confounds the assesment of the tumor clonality.
Proc Natl Acad Sci U S A, 100 (2003), pp. 3311-3314
[70.]
Q. Yang, N.A. Bermingham, M.J. Finegold, H.Y. Zoghbi.
Requirement of Math1 for secretory cell lineage commitment in the mouse intestine.
Science, 294 (2001), pp. 2155-2158
[71.]
C.S. Lee, N. Perreault, J.E. Brestelli, K.H. Kaestner.
Neurogenin 3 is essential for the proper specification of gastric enteroendocrine cells and the maintenance of gastric epithelial cell identity.
Genes Dev, 16 (2002), pp. 1488-1497
[72.]
H. Mutoh, B. Fung, F. Naya, M.-J. Tsai, J. Nishitani, A.B. Leiter.
The basic helix-loop-helix transcription factor BETA2/NeuroD is expressed in mammalian enteroendocrine cells and activates secretin gene expression.
Proc Natl Acad Sci U S A, 94 (1997), pp. 3560-3564
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